P815: PHARMACOKINETIC AND PHARMACODYNAMIC SIMILARITY OF ABP 959 AND ECULIZUMAB REFERENCE PRODUCT: UNBOUND ECULIZUMAB AND CH50 FROM THE RANDOMIZED, DOUBLE-BLIND, SINGLE-DOSE STUDY IN HEALTHY VOLUNTEERS
Authors: V. Hanes, J. Pan, D. Mytych, V. Chow
Journal: HemaSphere (2022)

Background: ABP 959 is being developed as a biosimilar to eculizumab reference product (RP). ABP 959 and the RP are humanized recombinant IgG2/4κ mAbs which bind with specificity to the human complement C5, blocking its cleavage to C5a and C5b and preventing the generation of the terminal complement complex (TCC), thereby blocking cell lysis. Excessive activation or insufficient control of C5 is believed to play a role in the pathogenesis of paroxysmal nocturnal hemoglobinuria (PNH), atypical hemolytic uremic syndrome (aHUS), generalized myasthenia gravis (gMG), and neuromyelitis optical spectrum disorder (NMOSD). Drug binding to C5 blocks this biological function and contributes to efficacy across these indications for which the RP is approved. Aims: The goal of this analysis is to further support the previously demonstrated pharmacokinetic (PK)/pharmacodynamic (PD) similarity of ABP 959 with eculizumab RP by providing additional data on similarity in PK exposure with respect to unbound eculizumab RP and 50% total hemolytic complement activity (CH50). Methods: This was a randomized, double-blind, single-dose, 3-arm, parallel-group trial in healthy adult male subjects, aged between 18 and 45 years, with a body mass index of 18 to 30.0 kg/m2, who were randomized following informed consent, to receive a 300-mg IV infusion of ABP 959, or FDA-licensed eculizumab RP (eculizumab US), or EU-authorized eculizumab (eculizumab EU). Serum samples for PK and PD evaluations were collected over 56 days. Primary objectives were to demonstrate PK and PD equivalence of ABP 959 versus eculizumab US and ABP 959 versus eculizumab EU, as assessed by area under the total serum concentration versus −time curve (AUC) from time 0 extrapolated to infinity (AUCinf) and an area between the effect curve (ABEC) of 50% total hemolytic complement activity (CH50). Secondary PK endpoints included AUC from time 0 to the time of the last observed quantifiable concentration (AUClast) and maximum observed concentration (Cmax). Pre-specified equivalence criterion for the primary PK and PD parameters was 90% confidence interval (CI) for geometric means (GM) ratio within 0.80 to 1.25. Other secondary endpoints included the safety, tolerability, and immunogenicity of the investigational products (IPs). Results: A total of 219 subjects were randomized (ABP 959, n=71; eculizumab US, n=74; eculizumab EU, n=74). As with PK and PD parameters of total eculizumab following a single 300 mg IV infusion of IP,1 PK/PD parameters for unbound eculizumab were similar between ABP 959 versus eculizumab US and ABP 959 versus eculizumab EU. The GM and GM coefficient of variation (%CV) of AUCinf (h.µg/mL) for unbound eculizumab was: 5072.1 (25) for ABP 959, 5527.6 (31) for eculizumab US, and 5070.3 (31) for eculizumab EU. The GM and %CV of ABEC of CH50 (%*h) was 17724.5 (38.75) for APB 959, 16549.4 (42.23) for eculizumab US, and 16361.1 (36.94) for eculizumab EU. The resulting 90 and 95% CI of GM ratios were within the bioequivalence criteria of 0.80 to 1.25. 1Eur J Haematol. 2020;105:66–74. Image:Summary/Conclusion: These additional clinical pharmacology results demonstrate bioequivalence of ABP 959 to eculizumab RP with regard to unbound eculizumab and CH50. These results further support the PK/PD similarity of ABP 959 with eculizumab RP.